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Abstract Background Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US. Methods The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period. Results Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity. Conclusions Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk. Trial registration NCT00216242

Immigrants and refugees seeking admission to the United States must first undergo an overseas medical exam, overseen by the US Centers for Disease Control and Prevention (CDC), during which all persons ≥15 years old receive a chest x-ray to look for signs of tuberculosis. Although individual screening sites often implement quality control (QC) programs to ensure radiographs are interpreted correctly, the CDC does not currently have a method for conducting similar QC reviews at scale. We obtained digitized chest radiographs collected as part of the overseas immigration medical exam. Using radiographs from applicants 15 years old and older, we trained deep learning models to perform three tasks: identifying abnormal radiographs; identifying abnormal radiographs suggestive of tuberculosis; and identifying the specific findings (e.g., cavities or infiltrates) in abnormal radiographs. We then evaluated the models on both internal and external testing datasets, focusing on two classes of performance metrics: individual-level metrics, like sensitivity and specificity, and sample-level metrics, like accuracy in predicting the prevalence of abnormal radiographs. A total of 152,012 images (one image per applicant; mean applicant age 39 years) were used for model training. On our internal test dataset, our models performed well both in identifying abnormalities suggestive of TB (area under the curve [AUC] of 0.97; 95% confidence interval [CI]: 0.95, 0.98) and in estimating sample-level counts of the same (-2% absolute percentage error; 95% CIC: -8%, 6%). On the external test datasets, our models performed similarly well in identifying both generic abnormalities (AUCs ranging from 0.89 to 0.92) and those suggestive of TB (AUCs from 0.94 to 0.99). This performance was consistent across metrics, including those based on thresholded class predictions, like sensitivity, specificity, and F1 score. Strong performance relative to high-quality radiological reference standards across a variety of datasets suggests our models may make reliable tools for supporting chest radiography QC activities at CDC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The first author is a left-handed, 51-year-old nephrologist who experienced a neurologic event. She underwent neurosurgery complicated by hemorrhage. Postoperatively, she developed persistent vertigo and unilateral tongue pain which persisted for over 5 years. Early neuroimaging revealed expected encephalomalacia but no neuroanatomical basis for her symptoms. A functional neurological disorder was suspected, and she was seen by several psychiatrists and psychotherapists. However, she suspected a neuroanatomical lesion would better explain her unrelenting symptoms. After seeing many neurologists, a neuroanatomical diagnosis was finally made. The theory and practice of medicine mandate that subjective complaint guides the modality and interpretation of objective evidence. The final neurologist knew where on neuroimaging to look because she was guided by the patient's complaints - vertigo and unilateral tongue pain. In this case, detailed scrutiny of neuroimaging by a neurologist, after encephalomalacia and gliosis were fully completed, gave a more accurate neuroanatomical diagnosis and a more realistic prognosis., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Abstract: One in 3 patients with lumbar spinal stenosis undergoing decompressive laminectomy (DL) to alleviate neurogenic claudication do not experience substantial improvement. This prospective cohort study conducted in 193 Veterans aimed to identify key spinal and extraspinal factors that may contribute to a favorable DL outcome. Biopsychosocial factors evaluated pre-DL and 1 year post-DL were hip osteoarthritis, imaging-rated severity of spinal stenosis, scoliosis/kyphosis, leg length discrepancy, comorbidity, fibromyalgia, depression, anxiety, pain coping, social support, pain self-efficacy, sleep, opioid and nonopioid pain medications, smoking, and other substance use. The Brigham Spinal Stenosis (BSS) questionnaire was the main outcome. Brigham Spinal Stenosis scales (symptom severity, physical function [PF], and satisfaction [SAT]) were dichotomized as SAT < 2.42, symptom severity improvement ≥ 0.46, and PF improvement ≥ 0.42, and analyzed using logistic regression. Sixty-two percent improved in 2 of 3 BSS scales (ie, success). Baseline characteristics associated with an increased odds of success were-worse BSS PF (odds ratio [OR] 1.24 [1.08-1.42]), greater self-efficacy for PF (OR 1.30 [1.08-1.58]), lower self-efficacy for pain management (OR 0.80 [0.68-0.94]), less apparent leg length discrepancy (OR 0.71 [0.56-0.91]), greater self-reported alcohol problems (OR 1.53 [1.07-2.18]), greater treatment credibility (OR 1.31 [1.07-1.59]), and moderate or severe magnetic resonance imaging-identified central canal stenosis (OR 3.52 [1.06-11.6]) moderate, OR 5.76 [1.83-18.1] severe). Using opioids was associated with lower odds of significant functional improvement (OR 0.46 [0.23-0.93]). All P < 0.05. Key modifiable factors associated with DL success-self-efficacy, apparent leg length inequality, and opioids-require further investigation and evaluation of the impact of their treatment on DL outcomes., (Copyright © 2020 International Association for the Study of Pain.)

Background: Children are susceptible to severe influenza infections and facilitate community transmission. One potential strategy to improve vaccine immunogenicity in children against seasonal influenza involves a trivalent hemagglutinin DNA prime-trivalent inactivated influenza vaccine (IIV3) boost regimen., Methods: Sites enrolled adolescents, followed by younger children, to receive DNA prime (1 mg or 4 mg) intramuscularly by needle-free jet injector (Biojector), followed by split virus 2012/13 seasonal IIV3 boost by needle and syringe approximately 18 weeks later. A comparator group received IIV3 prime and boost at similar intervals. Primary study objectives included evaluation of the safety and tolerability of the vaccine regimens, with secondary objectives of measuring antibody responses at four weeks post boost by hemagglutination inhibition (HAI) and neutralization assays., Results: Seventy-five children ≥6 to ≤17 years old enrolled. Local reactogenicity was higher after DNA prime compared to IIV3 prime (p<0.001 for pain/tenderness, redness, or swelling), but symptoms were mild to moderate in severity. Systemic reactogenicity was similar between vaccines. Overall, antibody responses were similar among groups, although HAI antibodies revealed a trend towards higher responses following 4 mg DNA-IIV3 compared to IIV3-IIV3. The fold increase of HAI antibodies to A/California/07/2009 [A(H1N1)pdm09] was significantly greater following 4 mg DNA-IIV3 (10.12 fold, 5.60-18.27 95%CI) compared to IIV3-IIV3 (3.86 fold, 2.32-6.44 95%CI). Similar neutralizing titers were observed between regimens, with a trend towards increased response frequencies in 4 mg DNA-IIV3. However, significant differences in fold increase, reported as geometric mean fold ratios, were detected against the H1N1 viruses within the neutralization panel: A/New Caledonia/20/1999 (1.41 fold, 1.10-1.81 95%CI) and A/South Carolina/1/1918 (1.55 fold, 1.27-1.89 95%CI)., Conclusions: In this first pediatric DNA vaccine study conducted in the U.S., the DNA prime-IIV3 boost regimen was safe and well tolerated. In children, the 4 mg DNA-IIV3 regimen resulted in antibody responses comparable to the IIV3-IIV3 regimen., Competing Interests: I have read the journal's policy and the authors of the manuscript have the following competing interests: this clinical study was conducted with funding and support by the National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research program, using resources provided by the American Recovery and Reinvestment Act of 2009 (Recovery Act), and contract #HHSN272201000049I awarded to the EMMES Corporation (AB, JM, EA, DB, BC, HK, PS, PW). AB and JM are salaried employees of the EMMES Corporation. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration., Methods: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination., Results: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group., Conclusions: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Children 6 through 35 months of age are recommended to receive half the dose of influenza vaccine compared with older children and adults., Methods: This was a 6-site, randomized 2:1, double-blind study comparing full-dose (0.5 mL) trivalent inactivated influenza vaccine (TIV) with half-dose (0.25 mL) TIV in children 6 through 35 months of age. Children previously immunized with influenza vaccine (primed cohort) received 1 dose, and those with no previous influenza immunizations (naive cohort) received 2 doses of TIV. Local and systemic adverse events were recorded. Sera were collected before immunization and 1 month after last dose of TIV. Hemagglutination inhibition antibody testing was performed., Results: Of the 243 subjects enrolled (32 primed, 211 naive), data for 232 were available for complete analysis. No significant differences in local or systemic reactions were observed. Few significant differences in immunogenicity to the 3 vaccine antigens were noted. The immune response to H1N1 was significantly higher in the full-dose group among primed subjects. In the naive cohort, the geometric mean titer for all 3 antigens after 2 doses of TIV were significantly higher in the 12 through 35 months compared with the 6 through 11 months age group., Conclusions: Our study confirms the safety of full-dose TIV given to children 6 through 35 months of age. An increase in antibody responses after full- versus half-dose TIV was not observed, except for H1N1 in the primed group. Larger studies are needed to clarify the potential for improved immunogenicity with higher vaccine doses. Recommending the same dose could simplify the production, storage, and administration of influenza vaccines.

Background: Young, healthy children shedding cytomegalovirus (CMV) in urine and saliva appear to be the leading source of CMV in primary infection of pregnant women., Findings: We screened 48 children 6 months - 5 years old for CMV IgG and measured levels of CMV IgG, IgM and IgG avidity antibodies, frequency of CMV shedding, and viral loads in blood, urine, and saliva. Thirteen of the 48 children (27%) were CMV IgG positive, among whom 3 were also CMV IgM positive with evidence of recent primary infection. Nine of the 13 seropositive children (69%) were shedding 102-105 copies/ml of CMV DNA in one or more bodily fluid. Among seropositive children, low IgG antibody titer (1:20-1:80) was associated with the absence of shedding (p = 0.014), and enrollment in daycare was associated with the presence of CMV shedding (p = 0.037)., Conclusions: CMV antibody profiles correlated with CMV shedding. The presence of CMV IgM more often represents primary infection in children than in adults. Correlating antibodies with primary infection and viral shedding in healthy children adds to the understanding of CMV infection in children that can inform the prevention of CMV transmission to pregnant women.

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Cohen's kappa coefficient, which was introduced in 1960, serves as the most widely employed coefficient to assess inter-observer agreement for categorical outcomes. However, the original kappa can only be applied to cross-sectional binary measurements and, therefore, cannot be applied in the practical situation when the observers evaluate the same subjects at repeated time intervals. This study summarizes six methods of assessing agreement of repeated binary outcomes under different assumptions and discusses under which condition we should use the most appropriate method in practice. These approaches are illustrated using data from the CDC anthrax vaccine adsorbed (AVA) human clinical trial comparing the agreement for two solicited adverse events after AVA between the 1-3 day in-clinic medical record and the patient's diary on the same day. We hope this article can inspire researchers to choose the most appropriate method to assess agreement for their own study with longitudinal binary data.

We evaluated whether coadministration of the yellow fever (YF) virus vaccine with human immunoglobulin (Ig) that contained YF virus-neutralizing antibodies would reduce post-vaccination viremia without compromising immunogenicity and thus, potentially mitigate YF vaccine-associated adverse events. We randomized 80 participants to receive either YF vaccine and Ig or YF vaccine and saline placebo. Participants were followed for 91 days for safety and assessments of viremia and immunogenicity. There were no differences found between the two groups in the proportion of vaccinated participants who developed viremia, seroconversion, cluster of differentiation (CD)-8(+) and CD4(+) T-cell responses, and cytokine responses. These results argue against one putative explanation for the increased reporting of YF vaccine side effects in recent years (i.e., a change in travel clinic practice after 1996 when hepatitis A prophylaxis with vaccine replaced routine use of pre-travel Ig, thus potentially removing an incidental YF vaccine-attenuating effect of anti-YF virus antibodies present in Ig).

Expression of high-risk HPV oncogenes results in a strong overexpression of cellular protein p16(INK4a). Immunohistochemical staining for p16(INK4a) is widely used as diagnostic marker. However, p16(INK4a) upregulation was also described as a biomarker of age. Here we analyzed p16(INK4a) expression in cervical smears to investigate if patient age may influence p16(INK4a)-based cervical cancer diagnosis. p14(ARF) was analyzed as a related supportive biomarker. Cervical scrapes were taken and stored in RNAlater. Total RNA was extracted, and cDNA was analyzed for expression of p16(INK4a) and p14(ARF) relative to β-actin, by real-time reverse transcriptase PCR SYBR-Green I assays. Patient-derived smears referred as HSIL (n=45) had 6.27-fold higher p16(INK4a) mRNA expression than smears of cytologically normal and HPV-negative persons (n=48). Expression of p14(ARF) was 4.87-fold higher. When women with normal diagnoses were stratified for age, a significantly enhanced p16(INK4a) (2.88-fold) and p14(ARF) (1.9-fold) expression was observed as a consequence of ageing. A significant age-dependent upregulation was also observed in older HSIL patients (2.54-fold). Our study revealed significantly enhanced expression of p16(INK4a)/p14(ARF) mRNA in cervical scrapes referred to as HSIL compared with normal women. An age-dependent bias has to be considered when quantifying these tumor suppressor genes, with respect to cervical cancer development.

Background: Host genetic characteristics and environmental factors may correlate with risk for cervical cancer development. Here we describe a retrospective screening study for single nucleotide polymorphisms (SNPs) in genetic markers TP53, MTHFR, CYP1A1, and CYP2E1 in 749 patients., Methods: A multiplex ligation-dependent polymerase chain reaction approach was applied. We used archived material from human papillomavirus tests and correlated SNP genotypes to the corresponding clinical data. Semantic integration was used to identify and evaluate the clinical status from electronic health records., Results: An association with cervical cancer and high-grade dysplasia was found for the rare homozygous CC genotype (rs4646903) in CYP1A1 (odds ratio [OR], 8.862). Odds ratios were also significantly elevated for heterozygous MTHFR CT genotype (rs1801133; OR, 1.457). No significant association was found in TP53 (rs1042522) and CYP2E1 (rs3813867). In addition, we found smokers at higher risk (OR, 2.688) and identified pregnancies as a significant risk factor (OR, 1.54)., Conclusions: Our protocol enables a feasible way for further retrospective large sample size evaluation of potential genetic markers. This study revealed genetic associations of a rare SNP genotype with cervical dysplasia in one of the largest patient sample to date that warrants further investigation.

Validation of PCR thermal cycler performance is crucial in order to obtain reliable results. In this study, high resolution melting curve (HRM) analysis is presented as a novel validation method for real-time PCR instruments. By applying HRM analysis using a defined PCR amplicon and EvaGreen dye, information about the temperature accuracy and thermal homogeneity of the heating block was obtained. This pilot study shows the potential of our technique for temperature validation of real-time quantitative PCR thermal cyclers. Our data correlated well with the temperature accuracy data obtained from the Mobile Temperature Acquisition System (MTAS; r2 = 0.93), which conforms to the National Institute of Standards and Technology criteria, and our method was reproducible in independent runs (r2 = 0.95). The advantages of this HRM-based method include: (i) temperature measurement under real world conditions in the reaction liquid in closed reaction tubes; (ii) temperature measurement of all wells; and (iii) applicability to all real-time PCR instruments capable of HRM analysis.

Limited sample size and low sensitivity of currently used functional assays challenge direct analysis of cytotoxic CD8+ T lymphocyte activity to quantify antigen-specific immunity after infection or vaccination. Our flow cytometry-based assay reproducibly detects at least three epitope-specific CD8+ T lymphocytes by their cytolytic function. As exemplified for viral epitopes restricted to the human leukocyte antigen (HLA)-A2, the HLA-A2+ human somatic cell hybrid T2 provided an about 10-fold more sensitive readout as compared to autologous B-lymphoblastoid cells or the human erythroleukemia cell line K562 transfected to express HLA-A2 when used as target cells. We named our assay VITAL-FR assay, referring to Hermans et al. (2004) and indicating the modification of using Far Red (FR) dye instead of CMTMR. Under optimal conditions the VITAL-FR assay proved 30 times more sensitive than the 51chromium-release assay to assess epitope-specific target cell lysis. The high overall sensitivity of the VITAL-FR assay basically depended on the negligible spectral overlap of the emission of a stable Far Red fluorescent reporter with the green tracer for target cell labelling. It also profited from long co-incubation of effector and target cells of up to 72, from prior in-vitro culture increasing the frequency of epitope-specific CD8+ T cells and from generic, easily accessible standardized target cells that were used with only 10(3) specific and 10(3) control target cells per individual experimental reaction. Our functional approach with the VITAL-FR assay therefore ideally suits for monitoring CD8+ T cell-mediated cytotoxicity in e.g. vaccination studies with known MHC-restricted immunogenic peptides in scientific and diagnostic applications., (2010 Elsevier B.V. All rights reserved.)

Objective: To identify risk factors for polymicrobial bloodstream infections (BSIs) in pediatric bone marrow transplant (BMT) outpatients attending a newly constructed clinic affiliated with a children's hospital., Methods: All 30 outpatients treated at a new BMT clinic during September 10-21, 2007, were enrolled in a cohort study. The investigation included interviews, medical records review, observations, and bacterial culture and molecular typing of patient and environmental isolates. Data were analyzed using exact conditional logistic regression., Results: Thirteen patients experienced BSIs caused by 16 different, predominantly gram-negative organisms. Presence of a tunneled catheter (odds ratio [OR], 19.9 [95% confidence interval {CI}, 2.4-infinity), catheter access (OR, 13.7 [95% CI, 1.8-infinity]), and flushing of a catheter with predrawn saline (OR, 12.9 [95% CI, 1.0-766.0]) were independently associated with BSI. The odds of experiencing a BSI increased by a factor of 16.8 with each additional injection of predrawn saline (95% CI, 1.8-827.0). Although no environmental source of pathogens was identified, interviews revealed breaches in recommended infection prevention practice and medication handling. Saline flush solutions were predrawn, and multiple doses were obtained from single-dose preservative-free vials to avoid delays in patient care., Conclusion: We speculate that infection prevention challenges in the new clinic, combined with successive needle punctures of vials, facilitated extrinsic contamination and transmission of healthcare-associated pathogens. We recommend that preservative-free single-use vials not be punctured more than once. Use of single-use prefilled saline syringes might prevent multiuse of single-use saline vials. Storage of saline outside a medication supply system might be advisable. Before opening new clinic facilities, hospitals should consider conducting a mock patient flow exercise to identify infection control challenges.

Background: We report the results of a phase I dose escalation, safety and immunogenicity trial of a new recombinant protective antigen (rPA102) anthrax vaccine., Methods: Hundred healthy volunteers were randomized in a 4:1 ratio to receive intramuscular doses of rPA102 in the following formulations: 5, 25, 50, or 75 microg of rPA102 in 82.5 microg aluminum hydroxide adjuvant at 0, 4, and 8 weeks; or the US licensed Anthrax Vaccine Adsorbed (AVA) at weeks 0 and 4., Findings: Local reactogenicity (mostly pain) was more common with AVA than with rPA102 following the first (94.7% versus 44.4%; p < 0.001) and the second (84.2% versus 35.4%; p < 0.001) vaccinations. Systemic reactogenicity (mostly headache) was more common among rPA102 vaccinees, but only following the first vaccination (49.4% versus 15.8%; p = 0.025). A dose-response relationship for anti-PA antibodies was present after the 2nd and 3rd vaccinations. Two weeks following the 2nd vaccination, the geometric mean titers (GMT) for lethal toxin neutralization activity (TNA), for the 5, 25, 50 and 75 microg rPA102 and AVA groups were 38.6, 75.4, 373.9, 515.3, and 855.2, respectively. The geometric mean concentrations (GMC) measured by anti-PA IgG ELISA were 3.7, 11.5, 25.9, 44.1, and 171.6, respectively. Two weeks following the 3rd vaccination, TNA GMTs for the four rPA102 groups, were: 134.7, 719.7, 2116.6, 2422.4; and ELISA GMCs were: 22.9, 104.7, 196.4, and 262.6, respectively., Interpretation: No clinically serious or dose-related toxicity or reactogenicity was observed. The TNA response after two injections of the 75 microg dose of rPA102 was similar to the response after two injections of AVA. The third rPA102 vaccination substantially increased the antibody response.

Dementia is a clinical syndrome with many causes. There often is overlap in the clinical manifestations of various forms of dementia, making them difficult to categorize. Neuroimaging can play an important role in distinguishing one form of dementia from another. Advanced imaging techniques continue to provide greater insight into the underlying pathologic processes in patients who have dementia. Conventional MRI and CT, however, still can contribute useful information when interpreting radiologists are familiar with the patterns of volume loss and signal or density changes that are characteristic of various forms of dementia.

Background: Congenital cytomegalovirus (CMV) infection is a leading cause of disabilities in children, yet the general public appears to have little awareness of CMV., Methods: Women were surveyed about newborn infections at 7 different geographic locations., Results: Of the 643 women surveyed, 142 (22%) had heard of congenital CMV. Awareness increased with increasing levels of education (P<.0001). Women who had worked as a healthcare professional had a higher prevalence of awareness of CMV than had other women (56% versus 16%, P <.0001). Women who were aware of CMV were most likely to have heard about it from a healthcare provider (54%), but most could not correctly identify modes of CMV transmission or prevention. Among common causes of birth defects and childhood illnesses, women's awareness of CMV ranked last., Conclusion: Despite its large public health burden, few women had heard of congenital CMV, and even fewer were aware of prevention strategies.

Neuroimaging can play an important role in distinguishing one form of dementia from another. Advanced imaging techniques continue to provide greater insight into the underlying pathologic processes in patients who have dementia. Conventional MRI and CT, however, can contribute useful information when interpreting radiologists are familiar with the patterns of volume loss and signal or density changes that are characteristic of various forms of dementia.

Objective: A meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4; Menactra; Sanofi Pasteur Inc, Swiftwater, Pa) was developed to improve the profile of currently licensed products. The objective of this study was to compare the tolerability, immunogenicity, and immune memory of MCV-4 with those of a quadrivalent polysaccharide vaccine (PSV-4; Menomune A/C/Y/W-135; Sanofi Pasteur Inc)., Design, Setting, Participants: A randomized, double-blind trial was performed at 11 clinical centers in the United States. The vaccine MCV-4 or PSV-4 was administered to 881 healthy 11- to 18-year-olds. Sera were collected prevaccination and 28 days postvaccination. Three-year follow-up and booster vaccination with MCV-4 were performed in a participant subset from each group and a control group., Main Outcome Measures: Proportion of participants with a 4-fold or greater increase in serum bactericidal antibody against each serogroup 28 days after initial vaccination, geometric mean serum bactericidal antibody titers, and safety assessments., Results: Both vaccines were well tolerated; most reactions were mild. More MCV-4 recipients reported solicited local reactions (68.9%) than PSV-4 recipients (30.2%). Both MCV-4 and PSV-4 were highly immunogenic; similar proportions of participants had 4-fold or greater increases in serum bactericidal antibody (range, 80.1%-96.7%) to the 4 serogroups. Three-year follow-up showed persistence of serum bactericidal antibody and booster responses to MCV-4 consistent with immune memory in participants previously vaccinated with MCV-4, but not in those who had previously received PSV-4., Conclusions: The vaccine MCV-4 was well tolerated and highly immunogenic. Persistence of bactericidal activity with MCV-4, but not PSV-4, was evident 3 years after the initial immunization. Booster response was demonstrated after a second vaccination with MCV-4.

We examined sera from 42 patients 1 to 30 months of age for rotavirus immunoglobulin M (IgM), IgA, IgG, and IgG subclasses and sought to determine if serum antibody could serve as a reliable marker for prediction of disease severity. Infants in the first few months of life usually had high maternal IgG titers and, when they were infected with rotavirus, had low IgM titers or no IgM in acute-phase sera and poor seroconversions 3 weeks later, suggesting that maternal antibodies had inhibited viral replication and antibody responses. All patients > or =6 months of age had IgM in acute-phase sera, indicating that IgM is a good marker for acute rotavirus infection. IgG was the best overall predictor of an infection, as the convalescent-phase sera of 81% of the patients had a fourfold rise in the IgG titer. IgA titers in convalescent-phase sera and conversion rates were higher among patients > or =12 months of age than among children younger than 12 months. IgG1 was the predominant subclass detected in the acute-phase sera of some children and in all 28 convalescent-phase serum samples examined. Patients with preexisting acute-phase IgG titers of > or =100 or > or =200 had diarrhea that was less severe or of a shorter duration. These results indicate that serum IgG is the most reliable marker for seroconversion and is a consistent proxy for protection against severe disease.

Giant cell angiofibroma (GCA) is a benign pathologic entity that has recently been reported in the literature. Originally described in the orbit, extraorbital sites of disease have also been reported. Herein, we describe the clinical, imaging, and pathologic findings of a case of GCA of the orbit.

A phase 2 evaluation of live attenuated parainfluenza type 3 (PIV3)-cold passage mutant 45 (cp45) vaccine was conducted in 380 children 6-18 months old; 226 children (59%) were seronegative for PIV3. Of the 226 seronegative children, 114 received PIV3-cp45 vaccine, and 112 received placebo. No significant difference in the occurrence of adverse events (i.e., runny nose, cough, or temperature > or =38 degrees C) was noted during the 14 days after vaccination. There was no difference between groups in the occurrence of acute otitis media or serous otitis media. Paired serum samples were available for 109 of the seronegative vaccine recipients and for 110 of the seronegative placebo recipients; 84% of seronegative vaccine recipients developed a > or =4-fold increase in antibody titers. The geometric mean antibody titer after vaccination was 1 : 25 in the vaccine group and <1 : 4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase 3 field trial.

Rotavirus is the most common cause of severe gastroenteritis in young children, but the pathogenesis and immunity of this disease are not completely understood. To examine the host response to acute infection, we collected paired serum specimens from 30 children with rotavirus diarrhea and measured the levels of nine cytokines (interleukin-1beta [IL-1beta], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) using a microsphere-based Luminex Flowmetrix system. Patients with acute rotavirus infection had elevated median levels of seven cytokines in serum, and of these, the levels of three (IL-6, IL-10, and IFN-gamma) were significantly (P < 0.05) higher than those in serum from control children without diarrhea. Patients with fever had significantly (P < 0.05) higher levels of IL-6 in serum than control children, and those with fever and more episodes of diarrhea had significantly (P < 0.05) higher levels of TNF-alpha than those without fever and with fewer episodes of diarrhea. We further demonstrated a negative association (P < 0.05) between the levels of IL-2 and the number of stools on the day on which the first blood sample was collected. Finally, patients with vomiting had significantly (P < 0.05) lower levels of IFN-gamma than those without vomiting. Our pilot study provides evidence that the types and magnitudes of cytokine responses to rotavirus infection in children influence or reflect the clinical outcome of disease. These findings suggest that certain cytokines may play an important role in the pathogenesis of and the protection against rotavirus disease in children and, consequently, may provide directions and insights that could prove critical to the prevention or treatment of this important disease.

Rates and severity of pneumococcal infections in children with sickle cell disease were examined before licensure of pneumococcal-conjugated vaccine (PVC). Rates of peak invasive infection rates in 1-year-old children with hemoglobin SS and mortality in those 0 to 10 years of age were 36.5 to 63.4 and 1.4 to 2.8 per 1000 person-years, respectively (>10 and 100 times as frequent as in the general population). Overall, 71% of serotyped isolates (n=80) were PVC serotypes and 71% of nonvaccine serotype strains were penicillin-sensitive. Clinical presentation in children with hemoglobin SS (n=71; more with hypotension) and hemoglobin SC (n=18; more with acute chest syndrome, otitis media) differed. Penicillin nonsusceptibility (38% of isolates) varied between geographic study sites. Penicillin prophylaxis appeared less effective against intermediate and resistant strains. Of all infected children, meningitis developed in 20% and 15% died (hemoglobin SS, n=15 and 11; hemoglobin SC, n=1 each). Factors associated with death included age >4 years (58%), serotype 19F, and not being followed by a hematologist (42% each). The pneumococcal-polysaccharide vaccine was 80.4% effective within 3 years after vaccination (95% CI, 39.7, 93.6). Children with sickle cell disease of all ages may benefit from PVC boosted with polysaccharide vaccination.

Background: In a previous clinical trial comparing COMVAX with its monovalent components, PedvaxHIB and RECOMBIVAX HB, one of 92 comparisons of post-vaccination adverse experiences revealed a higher rate of unusual, high-pitched crying following the second, but not the first or third doses of COMVAX compared with two monovalent control vaccines. Rates of prolonged crying were similar between groups at each visit., Objectives: To compare the frequencies of unusual, high-pitched crying between recipients of COMVAX plus placebo and recipients of PedvaxHIB plus RECOMBIVAX HB following the second vaccine doses (primary) and to summarize the frequency of unusual, high-pitched crying and prolonged crying after each vaccination visit., Design: We enrolled 1215 healthy infants in a randomized, double blind, placebo-controlled study. Participating infants received study vaccines at 2 and 4 months of age and other routine childhood vaccines at 6-7 weeks and 3 months of age. Crying was evaluated via questionnaire at the time of enrollment (baseline) and daily from days 0 to 2 after each injection., Results: Reports of unusual, high-pitched crying and prolonged crying were uncommon (<1%) prior to the first vaccination visit and were comparable in both treatment groups. After each injection, rates of unusual, high-pitched crying (range: 4.26-6.96%) and prolonged crying (range: 0-1.36%) appeared similar between treatment groups and for each vaccination visit. Crying resolved in all infants; no neurological impairment was reported., Conclusion: This study found no statistically significant differences in rates of unusual, high-pitched crying and prolonged crying in infants vaccinated with COMVAX plus placebo compared with infants vaccinated with its monovalent components, PedvaxHIB and RECOMBIVAX HB.

The cellular immune response to respiratory syncytial virus (RSV) infection was examined in infants aged 1-21 months who were hospitalized because of RSV infection or non-RSV-related illness. RSV- or control-stimulated peripheral blood mononuclear cells were examined to determine RSV-specific intracellular T helper-1 (Th1) and T helper- 2 (Th2) cytokine expression, chemokine messenger RNA (mRNA) expression, and cell surface markers. Patients hospitalized because of RSV infection had increased numbers of CD16(+) and CD56(bright) cells and had RSV-specific increases in Th1 (interleukin [IL]-2 and interferon-gamma) and Th2 (IL-4 and IL-6) cytokines and CC chemokines (macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and RANTES [regulated on activation, normally T cell expressed and secreted]) mRNA expression. The results suggest that RSV infection induces both Th1 and Th2 cytokine expression and CC chemokine expression.

We compared the use of serum and filter paper blood spots as specimen sources for the detection of measles- and rubella-specific IgM and IgG. We collected capillary blood into microtainer tubes and onto filter paper spots from 60 children and 60 healthy adults. The blood was collected from 12-15-month-old children approximately 3 weeks after primary vaccination with measles, mumps, rubella vaccine, and the sample-pairs were tested for measles-specific IgM and IgG antibodies by using a capture antibody EIA and an indirect EIA, respectively. We tested sample-pairs from a subset of participants for rubella- specific IgM and IgG antibodies by using commercially available capture IgM (Captia) and indirect IgG (Wampole) assays. The concordance of results from serum and filter paper blood spots was high for all assays: 98% for measles IgM, 93% for measles IgG, 94% for rubella IgM, and 93% for rubella IgG, and increased to between 96-100% for all four assays when indeterminate samples were excluded. The correlation coefficients for EIA signals were 0.99 and 0.77 for measles IgM and IgG, respectively, and 0.92 and 0.94 for rubella IgM and IgG, respectively. The cut-off values used for filter paper samples were the same as those used for serum samples for all tests except for the rubella IgM assay. The use of filter paper blood spots is a promising future option for the detection of measles- and rubella-specific antibodies., (Copyright 2001 Wiley-Liss, Inc.)

Nosocomial infections and antimicrobial resistance are major causes of mortality and morbidity and have become a major public health focus. To date, most national and international nosocomial infection surveillance and prevention activities have been focused on adults, despite the fact that pediatric patients are at high risk for nosocomial infections because of their immature immune systems and prevalent device usage. In 1997 the Hospital Infections Program at the Centers for Disease Control and Prevention and the National Association of Children's Hospitals and Related Institutions partnered to establish a Pediatric Prevention Network. Infection control professionals and their hospital administrators at all children's hospitals were invited to participate. The objectives of the network are to establish baseline infection rates; design, implement, and evaluate prevention interventions; establish benchmark rates and best practices; and serve as a site for multicenter studies to improve outcomes for hospitalized children. This network serves as a model for quality improvement systems in health care.

Background: Infection control (IC) structures and processes determine the effectiveness of surveillance efforts to prevent infections in health care settings., Methods: A survey was sent to 56 children's hospitals collaborating in the Pediatric Prevention Network (PPN)., Results: Completed surveys were returned from 48 hospitals. Responsibility for the IC program resided with the medical director (21%); vice president for patient care (18%); quality improvement director (17%); other senior hospital administrator (15%); or other hospital personnel (18%). Forty-two hospitals had an IC committee; 32 had antimicrobial restriction/control policies; and 21 had an antimicrobial restriction/control task force or committee. Components of antimicrobial restriction programs included infectious disease specialist approval, restricted formularies, selective susceptibility test reporting, and staff education programs. Many methods were used to detect infections, including microbiology laboratory reports (100%); record reviews (98%); informal reports from providers (90%); and readmission reviews (77%)., Conclusions: Children's hospitals vary widely in how they design and implement their IC functions. These variations influence adverse event detection and nosocomial infection rate calculations. If medical errors, including nosocomial infections, are to be detected and hospital rates compared, standardized methods to collect, analyze, and report data are needed. The PPN has initiated activities to standardize surveillance and IC practices in participating hospitals.

Background: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children. This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC)., Methods: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine. Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC. Routine childhood vaccines, including DTP, were coadministered. Temperatures and symptoms were recorded for 3 days after each immunization. Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4., Results: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose. Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown. Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster. Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively. One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster., Conclusions: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers. It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.

Objective: To confirm that children given a bivalent Haemophilus influenzae type b-hepatitis B vaccine (bivalent Hib-HB vaccine; COMVAX) concurrently with priming doses of diphtheria-tetanus-pertussis vaccine (DTP), a booster dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP), inactivated or oral polio vaccine (IPV or OPV) and measles-mumps-rubella vaccine (M-M-R(II)) have satisfactory antibody responses to all antigens., Design: 126 healthy 2-month-old infants were scheduled to receive bivalent Hib-HB vaccine concurrently with DTP (2 and 4 months of age), OPV or IPV (random allocation to OPV or IPV at 2 months of age; OPV at 4 and 14 to 15 months of age), DTaP and M-M-R(II) (14 to 15 months of age). A response was judged "adequate" if the lower bound of the 95% confidence interval on the proportion of vaccinees having a critical antibody level was <10 percentage points below prediction., Results: Antibodies to hepatitis B virus surface antigen, H. influenzae polysaccharide, diphtheria toxin, tetanus toxin, pertussis agglutinogens, pertussis toxin (as measured by enzyme immunoassay but not by Chinese hamster ovary cell assay), pertussis filamentous haemagglutinin after a booster dose of DTaP, poliovirus type 2, measles virus, and mumps virus all equalled or exceeded expected levels. Antibodies to rubella virus and pertussis filamentous haemagglutinin (after priming doses of DTP) fell slightly, and in the case of rubella significantly, below predicted levels. Antibodies to poliovirus types 1 and 3 were also below expectation after 2 doses of polio vaccine but were adequate following a third dose of vaccine., Conclusion: Concurrent administration of bivalent Hib-HB vaccine with priming doses of DTP, a booster dose of DTaP, OPV, IPV, or M-M-R(II) was well tolerated and, with the possible exception of rubella, did not substantially impair the antibody response to any antigen.

Background: The rapid emergence of both new infections and new technologies has revolutionized health care during the past 50 years. Increased use of the Internet has enabled health care professionals to educate, interact, and collaborate throughout the world in ways never before possible. Increased use of vancomycin has been associated with the emergence of organisms with decreased susceptibility to vancomycin, such as Enterococcus and staphylococcal species. The purpose of this article is to describe our experience using Internet technology to assess vancomycin use at children's hospitals in the United States., Methods: A Web-based evaluation was developed and distributed on the Internet to 57 Pediatric Prevention Network hospitals. The evaluation was structured to collect summary statistics on vancomycin use and admissions data by service for 1997 and 1998., Results: Twenty-four hospitals were able to provide archived vancomycin use and patient admissions data; completed evaluations were returned from 15 hospitals (62.5% response rate). Personnel at 6 (40%) hospitals completed the evaluation directly on the Internet., Conclusions: In our study, Internet technology facilitated a more efficient evaluation of vancomycin use, but fewer than half of the personnel at Pediatric Prevention Network hospitals completed the evaluation directly on the Internet. It is unclear whether personnel at these hospitals were limited in Internet access, support, or understanding. Efforts should be directed to educate health care personnel on the advantages of the Internet. Furthermore, many of the pharmacy databases used in our assessment were not standardized across hospitals nor systematically validated. Understanding that limitations still remain-within the source of the data studied, the health care system sampled, and the Internet tools available-is essential because the Internet offers health care professionals today a tool both to protect patients and to improve quality throughout the world.

Across-sectional study was performed of pediatric hematology-oncology patients who received vancomycin; use was compared to the Centers for Disease Control and Prevention (CDC) recommendations for vancomycin use. Thirty-seven patients received 308 doses of vancomycin. AR patients initially received vancomycin as empirical therapy; 100% of this use was not consistent with the CDC recommendations.

Objective: The objective of this article is to describe a pediatric neurosurgery patient population receiving vancomycin and examine the indications for and appropriateness of vancomycin use., Methods: A cross-sectional study was performed on the pediatric neurosurgery patients at Egleston Children's Hospital who received vancomycin from January 1 through December 31, 1996. Vancomycin use was compared with the Centers for Disease Control and Prevention Hospital Infection Control Practices Advisory Committee recommendations for vancomycin use., Results: Thirty patients received 115 doses of vancomycin. The median patient age was 8.0 years, and 17 (56.7%) were male. Vancomycin was used for prophylaxis in 28 (93.3%) patients and empiric therapy in 3 (10.0%) patients; one patient received vancomycin for surgical prophylaxis followed by empiric therapy for suspected meningitis. Vancomycin prophylaxis was initiated after the incision in 6 (21.4%) patients and was continued as prophylaxis for more than one dose in 26 (92.9%) patients., Conclusions: Vancomycin was used primarily as surgical prophylaxis in pediatric neurosurgery patients, and use was not consistent with the Hospital Infection Control Practices Advisory Committee recommendations. These data suggest that for certain subpopulations, such as pediatric neurosurgery patients, there is a need for more specialized recommendations. Furthermore, prudent vancomycin use is warranted to successfully decrease the risk of further emergence of vancomycin resistance. Because vancomycin use may be prevalent in this population, assessment of vancomycin use in pediatric neurosurgery patients followed by establishment of vancomycin clinical guidelines may help improve the appropriateness of vancomycin use in this population.